2-dialkylaminoalkoxy-6-substituted naphthalenes useful as new anticholesteremic agents



United States Patent 3,139,430 2 DIALKYLAMINOALKOXY 6 SUBSTITUTED NAPHTHALENES USEFUL AS NEW ANTI- CHGLESTEREMIC AGENTS William A. Bolhofer, Frederick, and James M. Sprague, 'Gwynedd Valley, Pa, assignors to Merck & Co., Inc., Railway, N.J., a corporation of New Jersey N0 Drawing. Filed Dec. 20, 1960, Ser. No. 76,996

26 Claims. (Cl. 260-2475) 1 This invention relates to new compounds for the study and treatment of hypercholesteremia and atherosclerosis. More specifically, this invention relates to new compounds of the formula :L A l (X) L 1m in which A may be naphthalene or tetralin having the R 0 and R substituents in the 2 and 6 positions, the said naphthalene or tetralin rings being possibly substituted with alkyl (R and halogens (X the R being a di-(lower alkyl) amino lower alkyl group or an N- morpholinyl lower alkyl group and the R being five or six membered carbocyclic rings which may carry a hydroxyl or a keto in the 3 position and which may also carry alkyl or halogen substituents, and which may have a cyano in the 3 position Whenever a hydroxyl is also on that carbon.

Atherosclerosis is a disease in which the arteries become blocked with deposits or plaques containing, among other things, cholesterol. Specifically, this disease is especially serious when it occurs in the coronary circulation system. All mammals have cholesterol in their blood, the major portion of which is derived by synthesis from acetate within the animal body, with only a small portion coming from dietary constituents. Numerous studies have suggested that there is a relationship between the plasma cholesterol concentration and atherosclerosis. There is, therefore, a need for agents to combat hypercholesteremia as an aid for the study of atherosclerosis and possibly the treatment of this disease.

In US. Letters Patent 2,687,436, Frederick C. Novello described a class of compounds which can be summarized as 6-alkoxy or hydroxy-Z-naphthyl cyclohexane deriva: tives. These compounds were described as being useful as intermediates in the synthesis of steroids and some of them were stated to have esterogenic activity. They are, however, completely inactive as agents for reducing blood cholesterol.

We have found that compounds of the structure de- 3,13%,439 Patented June 30, 1964 scribed above in the first paragraph are potent agents for reducing blood cholesterol. These compounds are related to the compounds describedby Novello in that the 6-alkoxy group of his compounds when replaced by a dialkylaminoalkoxy group form part of the compounds of our invention, but, whereasthe Novello compounds, as stated above, are completely inactive against hypercholesteremia, tests in vitro and in vivo have shown that the compounds of our invention are quite active.

It is an advantage of the compounds of our invention that they are easily administered orally. They can be utilized as pharmaceutically active salts such as the hydrochloride, hydrobromide, sulfate and the like. Since they can be administered orally, they can form part of the diet of the animal being tested. When applied parenterally they can be applied as oils or as solutions of the free base or of the salts.

It is a further advantage of the compounds of our invention that the representative of the class which has been most extensively studied exhibits no toxicity precluding general use in the study of hypercholesteremia. It showsno significant effect on the growth or upon food consumption. It shows no significant effect on the endocrine glands. It is relatively free of actions affecting the autonomic nervous system or tissues innervated by that system. It does not alter the renal functions. The other members of the class which have been tested show the same biological properties, as far as they have been tested, as this compound.

The various ring systems which form the chemical structures of the compounds of'our invention are synthesized in several ways depending on the rings and the substituents desired. In general, preparation of the diiferent kinds of rings and of the various functional derivatives, is shown in schematic Flow Sheets 1, H, III, and IV. Schematic Flow Sheet I shows the preparation of compounds in which R is a six-membered ring. The synthesis used is, in general, that shown in the Novello patent cited above. However, since the compounds of this invention comprise dialkylaminoalkyl ethers instead of Novellos methyl ethers, we have the further choice of when to introduce the dialkylaminoalkyl group. These can be introduced at the start, by cleaving the 6-acetyl-2- naphthyl methyl ether and alkylating the resultant 6-acetyl naphthol with a dialkylamino .allcylhalide. Alternatively, the R ring can be synthesized before such a change is made and further changes in the structure of the R substituent can be carried out at any of the methoxy, hydroxy, or dialkylaminoalkoxy stages as desired. The final product of the synthesis ending as a dialkylaminoalkyl ether.

(a) Synthesis of the Basic Ring System i? C-CH;

CHaO- HO- CH (EH30- IH ah 1 ii-OH;

II II 1| CH- 110- R10- (b) Interconversion of R s RnZCHa, H or R1 and at any stage in (1)) CH3 can be converted to H and then or later to R1 in the same manner as shown in (a) and after such conversion further of the above changes can be carried out.

Note: When the R2 ring contains no olefinic double bonds and also has no alcoholic hydroxyls, Reagent can be replaced with refluxing with HBr in CHsCOOH. In some cases, even though olefinic double bonds are present, this method can be used but Reagent (D is the method of choice.

11 Q Q PREPARATION OF COMPOUNDS IN WHICH R 7 IS A FIVE-MEMBERED RING 110 10 (a) Synthesis of the Basic Ring System 0 II J. Ch. Soc. 1940, 874. Symbols R1:di (lower-alkyl) amino lowcr-alkyl or N-moi'phohno O lower-alkyl. I Rn -H, CH3 01' R1. JIF-CHgX Reagents:

@ AlCls (cf. EX. 15 of U.S. 2,'687,486) or HBl. in acetic (31130 acid, if no ethylenic unsaturation, R101 01' R1Br (cf. Ex. 1 of this specification). (CH3)2NH.HC1+CI'I2O (cf. Ex. 1(a) of 2,687,436). Methyl or ethyl acetoacetate (cf. Ex. 1(b) of 2 687 ,436). 0 0 H2 and Pd catalyst (cf. Ex. 6 or 16 of 2,687,436). H H Aluminum iso-propoxide (cf. Ex. 13 or 19 of 2,687,436) 7 (when BuzH, it must be protected by acylation).

Minlon J. Am. Chem. Soc. 68, 2487 (1946) H2 and Pt catalyst (cf. Ex. 9 or 17 of 2,687,436). H2 and Adams catalyst (cf. EX. 11 or 18 of 2,687,430).

Bl: followed by heating with NaOH.

HBr in hexane, then NaOH. r HO- KBHi. 7o

(b) Interconversion of R55 Rho-l: I Rao- HBO- Rn CHS, H or R1 and at any stage in (1)) CH3 can be converted to H and then or later to R1 in the same manner as shown in (a) and after such conversion further 0f the above changes can be made. Symbols:

X=Br or C1. R1: rli(1ower alkyl) amino lower alkyl or N-morpholi Rn=CHa, H 01 R1.- Reagents:

@ Methyl or ethyl acetoacetate (cf. 1(b) of US. 2,68 AlCls in refluxmg toluene or xylene (of. Ex. 15 of R101 or R1Br (cf. Ex. 1 of this specification).

no lower alkyl.

Numbers lower than refer to Flow Sheet I table of reagents.

III

PREPARATION OF TETRALIN DERIVATIVES OHgO PREPARATION OF SOME SUBSTITUTED COMPOUNDS 5 (a) Introduction of Alkyls Into Six-Membered R Ring l H Aron-e-on-ooomn (1)) Introduction of Alkyls Into Five Membered R Rings E-CH-X l Preparation of Cyanohydrins A7 HCN AZ RsO 1L R110 L Similarly, any of the other five or six membered cyclic ketdolies when thus reacted yield the corresponding cyan0- hy 1'11.

HO CN not automatic and in such cases an extra hydrolysis and decarboxylatiou step is necessary (Novello, I. Am. Chem. Soc. 75, 1330, 5431 (1953)). This can be converted by various reductions to the cyclohexenol, cyclohexanol, cyclohexanone, cyclohexene and cyclohexane derivative, as illustrated in (b) of Flow Sheet 1. Further transformations by bromination of cyclohexene derivatives to get dibromocyclohexanes and dehydrobromination yields cyclohexadiene derivatives. The compounds of our invention in which R is phenyl or its derivatives are obtained by dialkylaminoalkylation of the known 6-phenyl- 2-naphthol (J. Chem. Soc. 1940, 874) and substitution products thereof prepared analogously.

Schematic Flow Sheet II shows the synthesis of derivatives in which R is a five-membered ring. A 6-halogenoacetyl-Z-naphthyl ether (either unsubstituted or carrying alkyl or halogen ring substituents) is reacted with acetoacetic ester or a derivative to give a 3-(6-alkoxy-2-naphthyl)-2-cyclopenten-l-one. This basic intermediate can then be subjected to the same kind of reductions as described in Flow Sheet I for the cyclohexanones and by these procedures, the corresponding cyclopentanone, cyclopentenol, cyclopentanol, cyclopentene, cyclopentadiene and cyclopentane are obtainable. As with the sixmembered R rings, the five-membered R ring can be synthesized upon either a methyl or a dialkylaminoalkyl naphthyl ether and the various transformations and reductions can be carried out on the methoxy, hydroxy or dialkylaminoalkoxy naphthyl compounds as desired, the final product being a dialkylaminoalkoxy compound.

Chemical Flow Sheet III shows another permissible variation within the class of compounds included in our invention. The central bicyclic ring system can be a tetralin as well as a naphthalene without destroying the hypochloesteremic activity. Part (a) in Flow Sheet III shows the synthesis of a tetralin with the reduced ring attached to the cyclohexane or cyclopentane ring. This synthesis starts with 6-methoxy-1,2,3,4-tetralone-2 and reacts upon this a cyclohexyl or cyclopentyl Grignard reagent. The resulting alcohol is dehydrated to a 3,4- dihydronaphthalene which, upon hydrogenation, gives 6-methoXy-2-cyclohexyl or cyclopentyl tetralin. After cleavage of the methoxyl group, the free hydroxy compound is reacted with a halogenoalkyldialkylamine to give a compound within the scope of our invention. As shown in Part (12) of schematic Flow Sheet III, the direct reduction with hydrogen over a copper chromite catalyst, of the compounds of our invention reduces the other ring of the naphthalene. Unsaturation in the R ring is simultaneously reduced and carboxyls become hydroxyls.

Further variations are permissible within the scope of our invention. Both the central rings and the R side ring may carry lower alkyl or halogen substituents.

The introduction of alkyl and halogen substituents in the naphthalene rings is carried out before synthesizing the R ring, i.e., the synthesis is run with the properly substituted 6-acetyl-2-naphthyl ether. An exception to this is the introduction-of halogens in the on position next to the ether oxygen by direct halogenation.

The introduction of alkyl substituents in the R rings is carried out by the means shown in schematic Flow Sheet IV, using in the standard synthesis reagents having additional alkyl carbons, so as to put the alkyl groups in the desired place. Thus, when a higher keto ester (such as vpropionylacetic ester of butyrylacetic ester) is used in place of the acetoacetic ester, the extra carbons appear as an alkyl group (A on the ring between the carbonyl and the bond to the naphthalene rings. When a-alkyl keto esters are used the ot-alkyl (A appears on the other side of the carbonyl group. In the case of six-membered R rings, the use of higher aldehydes in the Mannich synthesis puts an alkyl group (A on the second carbon from the naphthalene bond, while the use of a higher naphthyl ketone (propionyl or butyryl naphthyl methyl ethers, e.g.) put an alkyl group A on the carbon adjacent to the naphthyl bond, in either the five or six-membered R series. In any of these cases, all the further reductions and transformations which are shown in Flow Sheets I, H, and III can be carried out, yielding alkyl substituted cyclohexanols, cyclohexenols, cyclohexanes, cyclopentanones, cyclopentanes, etc. When such transformations are carried out to give the cyclopentanone or cyclohexanone derivatives, with or without alkyl or other substitution in R or in the naphthalene ring, the ketone so produced is then reacted with an alkyl magnesium bromide to give a tertiary alcohol in which the OH and the alkyl group (A have replaced the carbonyl oxygen.

Halogens are introduced into the R rings by one of two ways. Any of the unsaturated R rings can be dihalogenated directly with free halogen (e.g., chlorine, bromine). Thisreaction also adds a halogen substituent on the a position of the naphthalene ring next to the ether oxygen, in most cases. Such dihalogeno compounds can be used as intermediates for the preparation of dienes (by dehydrohalogenation with alkali), but they are themselves active compounds within the scope of our invention. In addition, any of the hydroxylated R rings can be reacted with a hydrogen halide to replace the hydroxyl by halogen. Thus, chloro, bromo, and iodo derivatives are readily preparable. When SP is used instead of a hydrogen halide, the hydroxyl is replaced by fluorine. Such halogeno derivatives, besides being compounds within the scope of our invention, are intermediates for unsaturated R ring compounds (by dehydrohalogenation with alkali). Conversely, the various unsaturated R ring I compounds (cyclopentenes, cyclopentadienes, cyclohexenes and cyclohexadienes) are themselves intermediates for halogeno compounds by the direct addition of hydrogen halide to the double bond.

The above preparations of substituted compounds of our invention are not limited to only the specific substituents discussed in each case. Several such substituents can be present at the same time in the R ring and simultane ously, the naphthalene ring may also carry alkyl and/ or halogen substituents.

Any of the ketones may be reacted with HCN to form a cyanohydrin instead of the ketone carbonyl which also falls within the scope of our invention. Reaction with HCN is conveniently carried out by an interchange with acetone cyanohydrin.

R in the general formula of the compounds of our invention is defined as a di-(lower alkyl) amino lower alkyl. It is necessary for anti-hypercholester'emia activity that the di-(lower alkyl) amino group be in the alkyl group, since the simple alkoxy compounds described by Novello have no such activity. R can be such groups as dimethylaminoethyl, propyl, isopropyl, butyl, dimethylaminoethyl, propyl, isopropyl, isobutyl, or butyl, dipropylaminoethyl, propyl, isobutyl or butyl, methylethylaminoethyl, propyl, or butyl, and the like. Preferably, it is diethylaminoethyl. The lower alkyl groups on the amino nitrogen may also be joined to form a ring such as morpholine and thus R may be also, in a separate aspect of our invention, N-morpholinoethyl, propyl, isopropyl, butyl, isobutyl and the like.

The compounds of our invention are tested for antih'ypercholesteremia activity in vitro by testing the inhibition of the formation of cholesterol from sodium acetate or sodium mevalonate in the presence of liver homogenate enzyme preparation. In vivo it is tested by adding it to the diet oftest animals and measuring the blood cholesterol and its variation with time. In general, the compounds of our invention should constitute from 0.01 to 0.1% of the dry diet of the mammal being treated. Dosages of the order of 250 mg. per day are approximately correct for humans with a range of 50-500 mg. The compounds of our invention are not all equivalent and the dosages must be varied to lit the activity of the compounds since some reduce blood cholesterol more than others.

Our invention can be illustrated by the following examples:

EXAMPLE 1 A sodium hydride-mineral oil mixture containing 0.044 mole of sodium hydride is added to a solution of 0.042 mole of 3-(6-hydroxy-2-naphthyl)cyclohexanone in ml. of isopropyl alcohol. A clear solution results to which is added 0.045 mole of B-diethylaminoethyl chloride. The reaction mixture, protected from atmospheric moisture, is stirred and heated under reflux for four hours. It is cooled, filtered, and the isopropyl alcohol is removed by concentration under a vacuum. The residual oil is dissolved in ether and the solution is Washed with water. Evaporation of the ether yields 3-[6-(fl-diethylaminoethoxy)-2-naphthyl]'cyclohexanone as an oil which slowly crystallizes to a solid. The hydrochloride salt is prepared by adding a 6 N solution of hydrogen chloride in ethanol to an ether solution of the free base. The precipitated solid is recrystallized to yield the pure hydrochloride.

When in place of the fi-diethylaminoethyl chloride in the above procedure, there is used an equivalent quantity of fl-dimethylaminoethyl chloride, l-chloro-Z-methyl- B-dimethylaminopropane, 3-diethylaminopropyl chloride, Z-diethylaminopropyl chloride or fl-dipropylaminoethyl chloride, the corresponding dialkylaminoalkoxy compound is obtained.

EXAMPLE 2 NCH:CH-O- The procedure of Example 1 is followed using an equivalent quantity of 3-(6-hydroxy-2-naphthyl)-2-cyclohexen-l-one in place of the hydroxy naphthyl cyclohexanone to yield 3-[6-(fi-diethylaminoethoxy)-2-naphthyl1- 2-cyclohexen-1-one which is readily converted in the same manner to a crystallized hydrochloride. When the other dialkylaminoalkyl chlorides are substituted for diethylaminoethyl chloride, the corresponding dialkylaminoalkyloxy naphthylcyclohexanones are obtained.

EXAMPLE 3 N C H: C H1 0 The procedure of Example 1 is followed using an equivalent quantity of 3-(6-hydroxy-2-naphthyl)-cyclohexanol in place of the hydroxy naphthyl cyclohexanone to yield 3-[-(fi-diethylaminoethoxy)-2-naphthyl]-cyclohexanol. When dimethylaminoethylchloride, diethylaminopropylchloride, 3 dirnethylamino-Z-methylpropylchloride, or 3-diethylamino-Z-methylpropylchloride is used in place of the diethylaminoethylchloride, the corresponding dialkylaminoalkyloxy compound is obtained.

1. 1 EXAMPLE 4 To a solution of 0.0241 mole of 3-[6-(fl-die'thylaminoethoxy) 2-naphthyl]-2-cyclohexen-1-one hydrochloride (the product of Example 2) in 200 ml. of methanol is added 0.0241 mole of sodium hydroxide in 5 ml. of water. A solution of 0.06 mole of potassium borohydride in 40 ml. of water containing 0.25 ml. of 10% sodium hydroxide is added dropwise. The solution is then stirred for six hours. The solvent is removed under reduced pressure and the residual syrup is dissolved in ether. The solution is washed with water. Evaporation of the ether results in the formation of a crystalline residue of 3- [6 (B-diethylaminoethoxy)-2-naphthyl]-2-cyclohexen-1- 01 In a similar fashion, the other dialkylamino alkyloxy naphthyl cyclohexenones of Example 2 are converted to the corresponding cyclohexenols.

EXAMPLE 5 The procedures of Examples 1 and 15 of US. Patent 2,687,436 are followed substituting an equivalent quantity of ethyl tat-ethyl acetoacetate for the methyl acetoacetate used in Example 1 of that patent. The product is 6-ethyl-3- (6-hydroxy-2-naphthyl) -2-cyclohexenl-one.

When ethyl a-propyl, a-methyl or oc-butyl acetoacetate is used in the synthesis of the starting material as described above, the corresponding 6-alkyl-cyclohexenone is readily obtained.

When these 6-propyl, methyl and butyl 3-(6-hydroxy- 2-naphthyl)-2-cyclohexen-1-ones so produced are used in equivalent quantities in place of the cyclohexenone derivative in the procedure of Example 17 of US. 2,687,436, the corresponding cyclohexanol derivatives are obtained. Similarly, when they are used in the procedure of Example 19 of that patent, the corresponding cyclohexenols are obtained and when they are used in the procedure of Example 16 of that patent, the corresponding cyclohexanones are obtained.

EXAMPLE 6 CgHs NC Hg C Hz 0 The procedures of Example 1 of this specification are followed using an equivalent quantity of 6-ethyl-3-(6-hydroxy-2-naphthyl)-2-cyclohexen-1-one (the product of Example 5) in place of the hydroxynaphthylcyclohexanone used therein to yield 6-ethyl-3-(6-diethy1amino ethoxy-2-naphthyl) -2-cyclohexen-l-one.

When Z-dimethylaminoethyl chloride, Z-dimethylaminopropyl chloride, 2- or 3-diethylaminopropyl chloride or di-iso-propylaminoethyl chloride is used in place of the Z-diethylaminoethyl chloride, the corresponding dialkylaminoalkoxy compound is obtained.

2 When the other products of Example 5 are used in equivalent quantity in place of the 6-ethyl cyclohexenone, the corresponding 6-propyl, 6-methy1 or 6-butyl cyclohexanol, cyclohexenol and cyclohexanone are obtained.

EXAMPLE 7 NCH2CHgO The procedure of Example 1 is followed, using in place of the hydroxynaphthyl cyclohexanone, an equivalent quantity of 2-cyclohexyl-6-hydroxynaphthalene (preparable by a Wolfl-Kishner reduction of the product of Example 6 of US. Patent 2,687,436, by refluxing that compound with hydrazine hydrate and KOH in diethylene glycol under which conditions the methoxy group is simultaneously cleaved (I. Am. Chem. Soc. 68, 2487 (1946)). The product is 2-cyclohexyl-6-fl-diethylaminoethoxynaphthalene. When the other dialkylaminoalkyl halides used in Example 1 are substituted for the diethylaminoethyl chloride, the corresponding dialkylaminoalkoxy compounds are obtained.

The procedure of Example 1 is followed using, in place of the hydroxynaphthylcyclohexanone, an equivalent quantity of 2-(1-cyclohexenyl)-6-hydroxynaphthalene (preparable by a Wolfl-Kishner reduction of the product of Example 1 of U8. Patent 2,687,436, by refluxing that product with hydrazine hydrate and KOH in diethylene glycol). The product is 6-(l-cyclohexenyl)-2-diethylaminoethoxynaphthalene, which is readily convertible to a hydrochloride salt by the procedure described in Example 1. used in place of diethylaminoethylchloride, the corresponding dialkylaminoalkoxy compound is obtained.

A Grignard reagent is prepared from 0.18 mole of magnesium turnings and 0.18 mole of ethyl bromide in 50 ml. of tetrahydrofuran under a nitrogen atmosphere. To this reagent is added a solution of 0.0295 mole of 3-[6-(fl-diethylaminoethoxy]-2-naphthyl)-cyclohexanone (the product of Example 1 of this specification) in 50 ml. of tetrahydrofuran. After stirring at reflux under nitrogen for 22 hours, the mixture is treated with aqueous ammonium chloride to hydrolyze the adduct. The tetrahydrofuran is removed under reduced pressure and the residual oil is taken up in ether. The ether solution is washed, dried, and the ether evaporated. The residual 1-ethyl-3-[6-(B- diethylaminoethoxy]-2 naphthyl)-cyclohexanol is converted into a citrate salt by stirring with an isopropyl alcohol solution of citric acid.

When the other dialkylaminoalkyl halides are EXAMPLE 10 N-CHaCEhO The procedure of Example 1 is followed using 6-pheny1- fl-naphthol (J. Chem. Soc., 1940, 374) in equivalent quantities, in place of the hydroxynaphthyl cyclohexanone, to give 6-phenyl-2-(ti-diethylaminoethoxy)naphthalene. When the other dialkylamino alkylchlorides used in Example 1 are substituted in this preparation for the diethylaminoethyl chloride, the corresponding dialkylaminoalkyl halide is obtained.

EXAMPLE 11 CgHg,

\NCH3CH1O 2 5 i One mole of 6-( l-cyclohexenyl)-2-diethylaminoethoxynaphthalene (the product of Example 8) is dissolved in sufiicient chloroform to dissolve it. A solution of 2.1 mole of bromine in chloroform is added gradually with stirring. The mixture is then stirred until bromination is complete. The solvent is evaporated under reduced pressure and the residue, essentially 6 (1,2-dibromocyclohexyl)-2-diethylarninoethoxy-l-bromonaphthalene hydrobromide is dissolved in isopropyl alcohol. Excess sodium ethoxide (about 3.5 moles) is added and the mixture is stirred at reflux until dehydrobromination is substantially complete. The solvent is then evaporated under reduced pressure and the residue is picked up in ether. A solution of hydrogen chloride in ethanol is added. The precipitated 6 cyclohexadiene 2 diethylaminoethoxy 1- bromonaphthalene hydrochloride is isolated by filtration.

EXAMPLE 12 The procedure of Example 1 of US. Patent 2,687,436 is followed using an equivalent quantity of ethyl, propionylacetate in place of the methyl acetoacetate. The product is the compound of the above structure 3 6-methoxy-2-naphthyl) -2-methyl-2-cyclohexenl-one) When ethylbutyrylacetate is used in place of the methyl acetoacetate, the corresponding 2-ethyl compound is obtained. When either of these products is treated by the procedure of Example 6 ofthe above patent, the corresponding cyclohexanone is obtained. Similarly, when either product is treated by the procedure of Example 9 of the above patent, the corresponding cyclohexanol is obtained and the procedure of Example 13 of that patent yields the corresponding cyclohexenol.

CHaO- 1d EXAMPL'E 13 The procedure of Example 15 of US. Patent 2,687,436 is followed, using an equivalent quantity of 3-(6-meth0xy- Z-naphthyl)-2-methyl-2-cyclohexen-l-one (the product of Example 12 of this specification) in place of the cyclohexenene derivative used therein as the starting material. The product is 3-(6-hydroxy-2-naphthyl)-2-methyl-2- cyclohexen-l-one. When the homologous 2-ethylcyclohexenone described in Example 12 of this specification is used instead, the corresponding hydroxynaphthyl ethyl cyclohexenone is obtained. 7

EXAMPLE 14 N-ouzomo The procedure of Example 1 is followed using an equivalent quantity of the product of Example 13 in place of the hydroxy naphthyl cyclohexanone used in Example 1 and using dimethylam'inoethyl chloride in place of the diethylaminoethyl chloride. The product obtained is 3- [6- (fl-dimethylaminoethoxy) -2-naphthyl] -2-methyl-2- cyclohexen-l-one.

EXAMPLE 15 A solution of 1 mole of 3-(6-methoxy-2-naphthyl)- cyclohexanol in hexane is saturated with dry hydrogen bromide and stirred until the reaction is substantially complete. Evaporation of the solvent yields 6-(3-bromocyclohexyl)-2-methoxynaphthylene. This product is then used in the procedure of Example 15 of US. Patent 2,687,436 in equivalent quantities in place of the methoxy naphthyl cyclohexenone to yield 6-(3-bromocyclohexyl)- Z-naphthol. This latter product is then used in the procedure of Example 1 in equivalent quantities, in place of the hydroxy naphthyl cyclohexanone used there as a starting material and using 3-dimethylamino-2-methyl-1- chloropropane in place of the diethylamino ethyl chloride, to form the desired 6-(3-bromocyclohexyl)-2-(S-di methylamino-Z-methyl-l-propyl naphthalene.

When 2-(diethylamino)ethyl chloride or 3-(diethylamino)-propyl chloride is used in equivalent quantities in place. of the dirnethylamino(methyl)propyl chloride in the procedure of Example 1, the corresponding dialkylaminoalkoxy (bromocyclohexyl)naphthalene is obtained.

When in the above procedure hydrogen chloride or hydrogen iodide is used in place of the hydrogen bromide, the corresponding S-chloro or 3-iodo compound is obtained and these compounds are converted by the procedures described above to the corresponding 3-chloro or 3-iodo cyclohexyl diethylaminoethoxy naphthalenes. When the procedure of Hasek et al. (J. Am. Soc. 82, 543 (1960)) is used instead of the saturation of a hexane solution with hydrogen bromide, the result of the reac- 15 tion with sulphur tetrafluoride is the 3-fluorocyclohexyl methoxynaphthalene which, like the other halogeno cyclohexylnaphthalenes described above is readily transformed by the above procedures to yield 6 (3-fluorocyclohexyl)-2-diethylaminoethoxynaphthalene.

EXAMPLE 16 (Br) Br(II) NCHzCHzO 0241s A mixture of 0.493 mole of 3-(6-methoxy-2-naphthyl)- 2 or 6-bromocyclohexanone (preparable by the treatment of 3-(6-methoxy-2-naphthyl)cyclohexanone with N-bromosuccinimide, the exact position of the bromine being uncertain), 850 ml. of 48% hydrobromic acid and one liter of glacial acetic acid is heated at reflux under nitrogen for 35-60 minutes. The reaction mixture is diluted with ice water and extracted with ether. The extract is washed with water and the naphthol is extracted into aqueous 1 N KOH solution. Acidification of the alkaline extract gives 3-(6-hydroxy-2-naphthyl)-2- or 6-bromocyclohexanone. This hydroxy compound is then used in the procedure of Example 1 of this specification in equivalent quantity in place of the hydroxynaphthylcyclohexanone used therein, to give 3-(6-diethylaminoethoxy-2- naphthyl)-2 or 6-bromocyclohexanone. When, in following the procedure of Example 1 of this specification, there is used an equivalent quantity of 3-(diethy1amino)- propyl chloride in place of the 2-diethylaminoethylchloride, the corresponding diethylaminopropoxy naphthyl bromocyclohexanone is obtained.

EXAMPLE 17 The procedure of Example 1 of US. Patent 2,687,436 is followed using an equivalent quantity of acetaldehyde in place of the formaldehyde to yield 5-methyl-3-(6- methoxy-Z-nziphthyl)-2-cyclohexene-1-one. This product is then used in the procedure of Example of US. Patent 2,687,436 in equivalent quantities, in place of the methoxynaphthyl cyclohexenone used therein, to give 5- methyl 3 (6-hydroxy-2-naphthyl)-2-cyclohexen-1-one. When this product is subjected to the procedure of Example 16 of the above-mentioned patent, the corresponding cyclohexanone is obtained. When this product is used in the procedure of Example 17 of the above-mentioned patent, the corresponding cyclohexanol is obtained and when it is used in the procedure of Example 19 of the above-mentioned patent, the corresponding cyclohexenol is obtained.

The procedure of Example 1 of this specification is then followed using fi-diisopropylaminoethyl chloride and each of the above hydroxynaphthyl methyl cyclohexenone, cyclohexanone, cyclohexenol and cyclohexanol to yield the corresponding 5-methyl-3-(6-diisopropylaminoethoxy- Z-naphthyl)-2-cyclohexen-1-one, l-cyclohexanone, l-cyclohexanol and Z-cyclohexen-l-ol.

1-6 When propionaldehyde and butyl aldehyde are used in the procedure of Example 1 of the above-mentioned patent in place of the formaldehyde, the corresponding 5- ethyl and S-propyl compounds are obtained by following the procedure described above.

EXAMPLE 18 02 5 /N-CHgCHzO C Ha C2115 The procedure of Example 1 of US. Patent 2,687,436 is used, replacing the 2-acetyl-6-methoxynaphthalene with equivalent quantities of 2-propionyl-6-methoxynaphthalene to yield 4-rnethyl-3-(6-rnethoxy-2-naphthyl)-2-cyclohexen-l-one. This product is then used in the procedure of Example 15 of US. Patent 2,687,436 to yield 4-methyl- 3-(6-hydroxy-2-naphthyl)-2-cyclohexen-1-one. When this product is used in the procedure of Example 16 of the above-mentioned patent, the corresponding cyclohexanone is obtained. When the procedure of Example 17 of that patent is followed the corresponding cyclohexanol is obtained and the procedure of Example 19 of that patent yields the corresponding cyclohexenol. When each of these compounds is used in the procedure of Example 1 of this specification in place of the hydroxynaphthyl cyclohexanone, used therein as a starting material, there is obtained respectively 3-(6-diethylaminoethoxy-Z-naphthyl)-6-methyl-2-cyclohexen-l-one; 3-(6-diethylaminoethoxy-2-naphthyl -6-methyll-cyclohexanone; 3 6-diethylaminoethoxy-Z-naphthyl)-6-methyl-1-cyclohexanol and 3- (6 diethylaminoethoxy 2 naphthyl) 6 methyl-2- cyclohexen-l-ol.

The procedure of Example 1 of US. Patent 2,687,436 is followed, using 2-propionyl-6-methoxynaphthalene in place of the acetyl-niethoxy naphthalene and ethyl propionyl acetate in place of the methyl acetoacetate, to yield 3 (6 methoxy 2 naphthyl) 2,4 dimethyl 2 cyclohexen-l-one. When this product is used in the procedure of Example 15 of the above patent in equivalent quantity in place of the methoxy naphthyl cyclohexenone, there is obtained 3-(6-hydroxy-2-naphthyl)-2,4-dimethy1- 2-cyclohexen-1-one. The procedure of Example 1 of this specification is then followed, using this product in place of the hydroxy naphthyl cyclohexanone used therein, to yield 3-(6-diethylaminoethoxy-Z-naphthyl)2,4-dimethyl- 2-cyclohexene-1-one.

Similarly, when the procedure of Example 1 of the above patent is followed again using 2-propionyl-6-methoxynaphthalene as above, but using ethyl-a-ethylacetoacetate in equivalent quantities instead of the propioacetate as above (or the acetoacetate as in that example) and the rest of the above procedure is then followed, there is obtained 6 ethyl 4-methyl-3-(6-diethylaminoethoxy-2- naphthyl 2-cyclohexen-1-one.

EXAMPLE 2O (Br) B1(H) N-CHzCHgO CgHs 6 (3 bromocyclohexyl) 2 methoxynaphthalene (prepared in Example 15 of this specification) is dissolved in ethanol. An excess of sodium ethoxide is added and the mixture is refluxed until dehydrobromination is complete. Evaporation of the solvent yields a residue which is slurried in water and filtered. The product, either 3-(6-methoxy-2-naphthyl)-l-cyclohexene or 4-(6- methoxy-Z-naphthyl)-l-cyclohexene, or a mixture of the two, is dissolved in chloroform and the solution is stirred while an excess of bromine (more than two molecular equivalents) in chloroform solution is added gradually. The reaction mixture is then stirred until the reaction is substantially complete. The solvent is removed under reduced pressure. The product, 6-(2,3- or 3,4-dibromocyclohexyl)-2-methoxy-l-bromonaphthalene is then used in the dealkylation procedure of Example 16 of this specification in equivalent quantities in place of the methoxynaphthyl cyclohexenone, to yield 6-(2,3- or 3,4-dibromocyclohexyl)-1-bromo-2-naphthol. This product is then used in the procedure of Example 1 of this specification, in equivalent quantity in place of the hydroxynaphthylcyclohexanone, to give 6-(2,3- or 3,4-dibromocyclohexyl)- Z-diethylaminoethoxy-l-bromonaphthalene.

When the above bromination procedure is followed, using equivalent quantities of the various cyclohexene, cyclohexenol, and cyelohexenone derivatives described in previous examples, there is obtained the corresponding l-bromonaphthyl dibromocyclohexane, cyclohexanol and cyclohexanone derivatives.

EXAMPLE 21 A mixture of 28 g. of 6-acetyl-2-methoxy naphthalene and 300 ml. of methylene chloride is stirred in the dark at 5 to -l C. A solution of 22.5 g. of bromine in 80 ml. of purified dioxane and -0 ml. of methylene chloride is added over 2 hours. A yellow solid separates and the temperature rises to C. The mixture is allowed to stand in the dark for one hour, after which it is poured into water with vigorous stirring. The organic layer is separated, washed with water and dried. The solvent is distilled under a vacuum and the residual oil crystallizes. To it is added ml. of hexane and the warmed solution is cooled. The crystalline .6-bromoacetyl-Z-methoxynaphthalene is filtered off and dried.

A mixture of 6 g. of acetoacetic ester in 200 ml. of ether and 2.2 g. of 53% sodium hydride in mineral oil is heated slightly. The bromoacetyl compound prepared 'above, dissolved in 100 ml. of warm benzene, is added and the mixture is refluxed for 3 hours. The mixture is cooled and filtered. The filtrate is washed with water, dried, and concentrated in vacuo to an oil which solidifies on standing. The product, 4-(6 methoxy-2 naphthyl)-4- oxo-2-acetylbutanoic acid, is recrystallized from ether.

To 10 g. of the above butanoic acid derivative is added 40 ml. of 2% aqueous potassium hydroxide under nitrogen. The mixture is stirred at reflux under nitrogen for 3 hours and then cooled to 5 C. The solid is collected by filtration and dried under a high vacuum. It is 3- (6- methoxy-2-naphthy1) -2-cyclopenten-1-one.

When this product is subjected to the procedure of Example 6 of the aforementioned patent, there is obtained the corresponding cyclopentanone. Similarly, when this product is subjected to the procedure of Example 9 of the above-mentioned patent, the corresponding cycle.- pentanol is obtained. The procedure of Example 13 of that patent yields the corresponding cyclopentenol. When the methoxynaphthylcyclopentenone and methoxynaphthyl cyclopentanone thus produced are refluxed in diethyleneglycol with hydrazine hydrate and KOH, the Wolfi- Kishner reduction yields the corresponding 1-(6-methoxy- 2-naphthy1)-1-cyclopentene and 2-cyclopentyl-6-methoxynaphthalene. When each of these products is used in equivalent quantities in the procedure of Example 15 of U.S. Patent 2,687,436, in place of the methoxynaphthylcyclohexenone, there is obtained respectively 3-(6-hydroxy-2-naphthyl)-2-cyclopentene-1-one; 3-(6-hydroxy-2- naphthyl) -1 O-cyclopentanone; 3-( 6-hydroxy-2-naphthyl l-cyclopentanol; 3-(6-hydroxy-2-naphthyl-2-cyclopentenl-ol; 6-(l-cyclopentenyl) Z-naphthol and 6-(1cyclopentyl) -2-naphthol.

EXAMPLE 22 CaHt N-CHzCHgO EXAMPLE 23 The procedure of Example 21 of this specification is followed, substituting an equivalent quantity of ethyl propioacetate for the ethyl acetoacetate to give 3-(6- methoxy 2 naphthyl) 2-methyl-2-cyclopentene-l-one. When this product is used in the procedure .of Example 6 of U.S. 2,687,436, there is obtained 3-(6-methoxy-2- naphthyl)-2 methyl 1 cyclopentanone. Similarly, .the procedure of Example 9 of the aforementioned patent yields 3-(6-methoxy-2-naphthyl)-2 methyl-1-cyclopenta- 1101 and the procedure of Example 13 of the abovernentioned patent yields 3-(6-methoxy-2-naphthyl)-2-methyl- Z-cycIopenten-l-ol. When the above cyclopentenone and cyclopentanone derivatives are refluxed in diethyleneglycol with hydrazine hydrate and KOH, the Wolff-Kishner reduction yields respectively 6-(Z-methyl-l-cyclopentenyl)- 2-methoxy-2-naphthalene and 6-(2-methylcyclopentyl)- Z-methoxynaphthalene.

When each of these products is used in the procedure of Example 15 of US. 2,687,436 in equivalent quantity in place of the methoxynaphthyl methylcyclohexanone, the methoxy group is cleaved and the corresponding free hydroxy compound is obtained. When each of these resultant free hydroxynaphthyl compounds is used in the procedure of Example 1 of this application, in equivalent quantities in place of the hydroxynaphthylcyclohexanone used therein as a starting material, there is obtained the corresponding diethylaminoethoxynaphthyl compound.

EXAMPLE 24 C 2115 N-CHgCH2O The procedure of Example 21 of this specification is followed, using an equivalent quantity of ethyl-u-ethyl acetoacetate in place of the ethyl acetoacetate, to yield 3-(6-methoxy-2-naphthyl)-5-ethyl-2-cyc1openten 1 one. When this product is used in the procedure of Example 9 of the above-mentioned patent, there is obtained 3-(6- methoxy-2-naphthyl)-5 ethyl 1 cyclopentanol. When either of these products is used in the procedure of Example 15 of U.S. Patent 2,687,436 there is obtained the corresponding 6-hydroxynaphthyl compound and when these hydroxynaphthyl compounds are used in the procedure of Example 1 of this specification, in equivalent quantities, in place of the hydroxynaphthyl cyclohexanone used in that example as a starting material, there are obtained respectively 5 ethyl 3-(6-diethylaminoethoxy-2- naphthyl)-2-cyclopenten-1-one and 5-ethyl-3-(6-diethylaminoethoxy-Z-naphthyl) l-cyclopentanol.

EXAMPLE 25 N- C H O H: O

The procedure of Example 15 of this specification is used, replacing the methoxynaphthylcyclohexanol with an equivalent quantity of 3-(6-methoxy-2-naphthyl)-lcyclopentanol (prepared in Example 21 of this specification), to yield in successive steps, as in Example 15, 5-(3- bromo-l-cyclopentyD-Z methoxynaphthalene, which, in turn, is cleaved to 5-(3-bromo-cyclopentyl)-2-naphthol and thus finally yields 5-(3-bromo-cyclopentyl)-2-diethylaminoethoxy naphthalene. As in Example 15, when hydrogen chloride and hydrogen iodide are substituted for the hydrogen bromide in the above procedure, the corresponding chloro and iodo compounds are obtained. Similarly, when the substituted cyclopentanol is treated with sulfurtetratluoride by the method of Hasek et al., the corresponding fluoro-cyclopentyl compound is obtained and each of these halogen compounds is converted, as in Example 15 of this specification, through the free hydroxyl compound to the diethylaminoethoxy-3-halogeno cyclopentyl compound.

20 EXAMPLE 26 The procedure of Example 15 of this specification is followed, using 5-ethyl-3-(6-methoxy-2-naphthyl)-l-cyclopentanol (prepared in Example 24) in equivalent quantities in place of the methoxynaphthylcyclohexanol. The resultant product of the reaction with hydrogen bromide by the procedure of Example 15 is 2-(2-bromo-3-ethylcyclopentyl)-6-methoxy naphthalene, which when used in the procedure of Example 15 of U8. 2,687,436, yields 2- (2-bromo-3-ethyl cyclopentyl)-6-naphthol, which, in turn, when used in the procedure of Example 1 in equivalent quantities in place of the hydroxynaphthylcyclohexanone, yields 6-(2-bromo-3-ethyl cyclopentyl)-2-diethylaminoethoxynaphthalene.

EXAMPLE 27 N-OH2CH2O C3115 t-Butyl hypochlorite (0.05 mole) is added to a wellstirred suspension of 0.05 mole of 2-hydroxy-6-cyclohexylnaphthalene in 50 ml. of carbon tetrachloride. The clear solution is heated under reflux for 15 minutes and then concentrated under reduced pressure to yield l-chloro-2- hydroxy-6-cyclohexylnaphthalene which is purified by recrystallization from alcohol and then benzene.

The procedure of Example 1 of this specification is followed using the above 1-chloro-2-hydroxy-6-cyclohexyl naphthalene in place of the hydroxynaphthyl cyclohexanone to give 1-chloro-2-diethylaminoethoxy-6-cyclohexylnaphthalene.

EXAMPLE 28 CzHi N- 0 Hz C H2O 21 used in Example 13 it yields the corresponding cyclohexenol. When each of these products is used in the procedure of Example of US. 2,687,436, there are obtained respectively 3-(6-hydroxy=8-bromo-2-naphthyl)- 2-cyclohexene-1-one; 3-(6-hydroxy=8-bromo-2-naphthyl)- 1-cyclohexanone; 3-(6-hydroxy-8-bromo-2-naphthyl)-1- cyclohexanol and 3-(6-hydroxy-8-bromo-2-naphthyl)-2- cyclohexene-l-ol. When each of these products is used in the procedure of Example 1 of this specification in equivalent quantity in place of the hydroxy naphthyl cyclohexanone, there is obtained the correspondingly sub stituted compound wherein the hydroxy group is replaced with a diethylaminoethoxy group.

Similarly, when the diazotized 3-methoxy-l-naphthylamine is treated with cuprous iodide, the corresponding 4-iodo starting material is obtained which results in an iodo substituted naphthyl compound. When 3-methoxyl-naphthylamine is diazotized and treated with fluoroboric acid, and the resulting 3-methoxy-l-fluoronaphthalene is used in equivalent quantities in the above procedure in place of the bromo compound, the corresponding fluoro compound is obtained.

Similarly, when the above procedures are carried out upon 1-methyl-6-acetyI-Z-methoxynaphthalene (obtainable by the condensation of acetyl chloride on l-methyl-finaphthol methylether), 1-.chlor.oe6-acetyl-2-methoxynaphthalene (obtainable by the condensation of acetyl chloride with 1-chloro-2-naphthol-methylether), l-methyl-3-bromo- 6-acetyl-Z-methoxynaphthalene (obtainable by methylation of 3-bromo-l-methyl-Z-naphthol, followed by the condensation of acetyl chloride with the resulting 1-methyl-3-brorno-2-rnethoxynaphthalene), l-methyl-4- chloro-6-acetyl-2-methoxynaphthalene (obtainable by methylation of 4-chloro-1-methyl-2-naphthol with dimethyl sulfate, followed by the reaction of acetyl chloride with the resulting 1-methyl-2-methoxy-4-chloronaphthalene) and 1,3-dichloro-2-methoxy 6-acetylnaphthalene (obtainable by methylation of 1,3-dichloro-2-naphthol with dimethyl sulfate, followed by the condensation of acetyl chloride with the resulting 1,3-dichloro-2-methoxynaphthalene), the correspondingly substituted products are obtained.

EXAMPLE 29 C 2H5 A N 0 H1O Hz 0 z a 2-hydroxy-6-cyclohexylnaphthalene is reduced in an alcohol-solution at 200 C. and 3300 psi with copper chromite catalyst in an atmosphere of hydrogen. The catalyst is removed 'by filtration and the alcohol is removed by distillation. The waxy residue is recrystallized from ether to yield '2-hydroxy-6-cyclohexyl-1,2,3,4-tetrahydronaphthalene.

A suspension of sodium hydride (0.02 mole) is added to 0.02 mole of 2-hydroxy-6-cyclohexyl-1,2,3,4- tetrahydronaphthalene in 50 ml. of toluene. Diethylarninoethylchloride is then added and the mixture is heated under reflux for 24 hours The resulting sodium chloride is removed by filtration and the toluene is distilled off in vacuo. The oily residue is distilled through a short path still to obtain as Z-diethylamino ethoxy-6- cyclohexyl-l,2,3,4-tetrahydronaphthalene, the fraction boiling at 150 C. and-0.05 mm.

22 EXAMPLE 30 N-CHgCHzO The procedure of Example 1 is followed using in place of diethylaminoethylchloride an equivalent quantity of N-(fl-chloroethyhmorpholine to yield 3-(N-morpholinylethoxy-Z-naphthyl)cyclohexanone which can be purified by recrystallization from isopropyl alcohol. Similarly, when in the above procedure, in addition, there is substituted for the hydroxynaphthyl cyclohexanone an equivalent quantity of 3-(6-hydroxy-2-naphthyl)-2-cyclohexene-l-one or 3-(6-hydroxy-2-naphthyl)-l-cyclohexanol or 3-(6-hydroxy-2-naphthyl)-2-eyclohexene-1-ol, the correspondingly substituted products are obtained.

Similarly, also, when any of the other 6-hydroxy- 2-naphthyl cyclohexanes, cyclohexenes, cyclohexadienes, cyclohexanones, cyclohexenones, cyclohexanols, cyclohexenols, cyclopentanes, cyclopentenes, cyclopentanones, cyclopentenones, cyclopentanols, cyclopentenols and benzenes described or used in Examples 1 through 29 inclusive, whether otherwise substituted or not. are used in the procedure of Example 1 in equivalent quantity in place of the hydroxynaphthyl cyclohexanone and N-(B-chloroethyl)-morpholine is used in place of the diethylaminoethylchloride in equivalent quantity the corresponding -6-(N-morpholinyl-ethoxy-Z-naphthyl) compound is obtained.

EXAMPLE 31 A solution of 0.0266 mole of 3-(6-(B-diethylamino- ,ethoxy)-2-naphthyl)-cyclohexanone (the product of Example 1) in 0.118 mole of acetone cyanohydrin is placed under a vacuum of 13 mm. for 18 hours. The reaction mixture is then stirred with ml. of water. The water layer is decanted from the gum which separates. A solution of the gummy product in ether is washed with water. The ether is distilled and 1-cyano-3-(6-(fi-diethylaminoethoxy)-2-n aphthyl) cyclohexanol is obtained as a syrup. A crystalline hydrochloride is prepared by adding HCl 'to an isopropyl ether solution of the syrup.

When any of the other cyclohexanones, cyclohexenones, cyclopentanones, or .cyclopentenones prepared in any of the preceding examples, is substituted in equivalent quan- ,tity for the above cyclohexanone, the corresponding cyanohydrin is obtained.

EXAMPLE 32 The above products are tested for effectiveness in the reduction of blood cholesterol by the following procedure:

Holtzman male albino rats, weighing -140 grams are maintained on Purina Laboratory Chow for five days. The rats are then randomized according to weight into groups of 20 rats and placed upon Purina Laboratory .Chow diet to which 10% lard has been added. The compound being tested is administered by incorporation in the diet. After =10 days, blood samples are taken by cardiac puncture and'the plasma is analyzed for total cholesterol by Abell et al. '(J Biol. Chem. 195, 357, 1952).

The results of such testing for a number of the compounds prepared above are given in the following table:

Table for Example 32 in which A is a radical consisting of two siX-membered carbocyclic rings having two adjacent carbon atoms in common, at least one of said rings being aromatic, the R and R substituents being in a 2,6 relationship to one another, R is lower alkyl, X is halogen, m and n are each whole numbers greater than minus one and less than three, R is a di(lower alkyl) amino lower alkyl group, and R is a carbocyclic ring of the skeletonwherein p is a positive whole number less than three, Y represents a hydroxyl, Y represents a carbonyl oxygen, r and s are each whole numbers greater than minus one and less than two, one of r and s being Zero whenever the other is one but both can be zero, R is lower alkyl, X is halogen, t and u are each whole numbers greater than minus one and less than three, the number of double bonds joining carbons of said ring skeleton being greater than minus one and less than four and when any double bonds are present, one such double bond joins the carbon by which said skeleton is joined to A to the carbon adjacent to that to which Y is attached, Z is cyano attached to the same carbon as Y v is zero when r is zero and when s is one and is otherwise a whole number greater than minus one and less than two being one only when r is one, and any valence bonds in said A and said R radicals not satisfied by aforedefined structural characteristics are linked to hydrogen.

2. A compound of the formula in which A is a radical consisting of two six-membered carbocyclic rings having two adjacent carbon atoms in common at least one of said rings being aromatic, the R O- and R substituents being in a 2,6 relationship to one another, R is lower alkyl, X is halogen, m and n are each whole numbers greater than minus one and 24 less than three, R is a di(lower alkyl) amino lower alkyl group, and R is a radical of the formulain which R; is lower alkyl, X is halogen, and t and u are each whole numbers greater than minus one and less than three, and any valence bonds in said A rings not satisfied by the above-defined structural characteristics, are linked to hydrogen.

3. A compound of the formulain which A is a radical consisting of two six-membered carbocyclic rings having two adjacent carbon atoms in common, at least one of said rings being aromatic, the R 0 and R substituents being in a 2,6 relationship to one another, R is lower alkyl, X is halogen, m and n are each whole numbers greater than minus one and less than three, R is a di(lower alkyl) amino lower alkyl group and R is a radical of the formulain which R, is lower alkyl, X is halogen and t and u are each whole numbers greater than minus one and less than three, and any valence bonds in said A rings not satisfied by the above-defined structural characteristics are linked to hydrogen.

4. A compound of the formula- IMO- Rg A I in which R is lower alkyl, X is halogen, and t and u are each whole numbers greater than minus one and less than three, and any valence bonds in said A ring not satisfied by the above-defined structural characteristics are linked to hydrogen.

5. A compound of the formulain which A is a radical consisting of two six-membered carbocyclic rings having two adjacent carbon atoms in common, at least one of said rings being aromatic, the R 0 and R substituents being in a 2,6 relationship to one another, R is lower alkyl, X is halogen, m and n are each whole numbers greater than minus one and less than three, R is a di(lower alkyl) amino lower alkyl group and R is a radical of the formula 2)n in which R, is lower alkyl, X is halogen, Z is cyano attached to the same carbon as the hydroxyl and t, u and v are each whole numbers greater than minus one and less than three and any valence bonds in said A rings not satisfied by the above-defined structural characteristics are linked to hydrogen.

6. A compound of the formula (X2) u in which R, is lower alkyl, X is halogen, Z is cyano attached to the same carbon as the hydroxyl-and t, u and v are each whole numbers greater than minus one and less v 26 one another, R is lower alkyl, X is halogen, m and n are each whole numbers greater than minus one and less than three, R is a di (lower alkyl) amino lower alkyl group, and R is a radical of the formula- (Xi) u in which R; is lower alkyl, X is halogen, t and u are each whole numbers greater than minus one and less than three, and any valence bonds in said A rings not satisfied than three, and any valence bonds in said A, rings not satisfied by the above-defined structural characteristics are linked to hydrogen. a

7. A compound of the formula R10- a) n 1) in L J in which A is 'a radical consisting of two six-membered carbocyclic rings having two adjacent carbon atoms in common, at least one of said rings being aromatic, the R 0 and R substituents being in a 2,6 relationship to one another, R is lower alkyl, X is halogen, m and n are each whole numbers greater than minus one and less than three, R is a di(lower alkyl) amino lower alkyl group, and R is a radical of the formula-- in which R; is lower alkyl, X is halogen, t and u are each whole numbers greater than minus one and less than three, and any valence bonds in said R rings not satisfied by the above defined structural characteristics are linked r to hydrogen. a

8. A compound of the formula L J (X0111 in which A is a radical consisting of two six-membered carbocyclic rings having two adjacent carbon atoms in common, at least one of said rings being aromatic, the R 0 and R substituents being in a 2,6 relationship to by the above-defined structural characteristics are linked to hydrogen.

9. A compound of the structurein which A is a radical consisting of two six-membered carbocyclic rings, having two adjacent carbon atoms in common, at least one of said rings being aromatic, the R 0 and R substituents being in a 2,6 relationship to one another, R is lower alkyl, X is halogen, m and n are each whole numbers greater than minus one and less than three, R is a di (lower alkyl) amino lower alkyl group, and R is a radical of the -formula in which R, is lower alkyl, X is halogen, t and u are each whole numbers greater than minus one and less than three, and any valence bonds in said A rings not satisfied by the above-defined structural characteristics are linked to hydrogen.

10. The compound of the formula-- N-O1H -O 11. The pharmaceutically acceptable acid addition salts of the compound of claim 10.

12. The compound of the formula- N-C3H4-0 13. The pharmaceutically acceptable acid addition salts of the compound of claim 12.

14. The compound ofthe formula-- 15. The pharmaceutically acceptable acid addition salts of the compound of claim 14.

The compound of the formula- NC2H4-0 0, 15 The compound of the formula N-C2H4O The compound of the formula- The compound of the formula- The compound of the formula- The compound of the formula- 23. A compound of the formulain which A is a radical consisting of two six-membered carbocyclic rings having two adjacent carbon atoms in common, at least one of said rings being aromatic, the R 0 and R substituents being in a 2,6 relationship to one another, R3 is lower alkyl, X is halogen, m and n are each whole numbers greater than minus one and less than three, R is N-morpholinyl-lower alkyl and R is a carbocyclic ring of the skeletonwherein p is a positive whole number less than three, Y represents hydroxyl, Y represents a carbonyl oxygen, r and s are each whole numbers greater than minus one and less than two, one of r and s being zero whenever the other is one, but both can be zero; R is lower alkyl, X is halogen, t and u are each whole numbers greater than minus one and less than three, Z is cyano attached to the same carbon as Y v is zero when r is zero and when s is one and is otherwise a whole number greater than minus one and less than two, being one only when r is one, the number of double bonds joining carbons of said ring skeleton being greater than minus one and less than four and when any double bonds are present one such double bond joins the carbon by which said skeleton is joined to A to the carbon adjacent to that to which Y is attached, and any valence bonds in said A and said R radicals not satisfied by the aforedefined structural characteristics are linked to hydrogen.

24. A compound of claim 23 in which R is cyclohexen-l-on-3-y1-1.

25. The compound- HO ON CgH5 N-CHzCHgO CgHg References Cited in the file of this patent UNITED STATES PATENTS 2,687,436 Novello Aug. 24, 1954 2,703,329 Schultz Mar. 1, 1955 2,744,139 Binkley et a1. May 1, 1956 2,773,900 Mills Dec. 11, 1956 2,912,453 Moifett Nov. 10, 1959 2,947,749 Winthrop Aug. 2, 1960 

1. A COMPOUND OF THE FORMULA-
 25. THE COMPOUND- 